A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma.
Hani HarbEmmanuel Stephen-VictorElena CrestaniMehdi BenamarAmir MassoudYe CuiLouis-Marie CharbonnierSena ArbagSafa BarışAmparito CunnighamJuan Manuel Leyva-CastilloRaif S GehaAmirhosein J MousaviBoris GuennewigKlaus Schmitz-AbeConstantinos SioutasWanda PhipatanakulTalal A ChatilaPublished in: Nature immunology (2020)
Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.
Keyphrases
- induced apoptosis
- cell proliferation
- oxidative stress
- cell cycle arrest
- transcription factor
- particulate matter
- chronic obstructive pulmonary disease
- stem cells
- lung function
- signaling pathway
- poor prognosis
- endoplasmic reticulum stress
- dendritic cells
- cell death
- risk assessment
- immune response
- diabetic rats
- mesenchymal stem cells
- pi k akt
- binding protein
- allergic rhinitis
- high glucose